In recent years, the mortality rate relating to cardiovascular diseases has increased year by year. If diseases caused by arteriosclerosis such as cardiac infarction and brain infarction are included, cardiovascular diseases are ranked at the top of the causes of death in adults.
Arteriosclerosis is caused by a variety of factors. Among them, increase in plasma lipid level, inter alia, plasma cholesterol level, is conceivably one of the most dangerous factors.
One cause of elevated plasma cholesterol level is a genetic disease. In this case, grave patients are given diet therapy, and simultaneously, drugs such as a cholesterol synthesis inhibitor, Nicomol, Clofibrate, an ion-exchange resin, and an anabolic steroid are employed. However, these drugs cause adverse side effects such as toxicity to the liver, gastrointestinal disorders, and carcinogenicity.
Another important cause of elevated plasma cholesterol level is excessive fat consumption caused by the recent dietary custom of consuming a large quantity of eggs, butter, meat, etc., to the extent that excessive fat consumption has become the general habit for younger people. Alimentary hypercholesterolemia induced by excessive fat consumption generally does not become grave in comparison with that caused by genetic factor. But alimentary hypercholesterolemia induces a gradual accumulation of cholesterol in the vascular wall from a young age and problematically causes arteriosclerosis in adulthood, and then may cause cardiac infraction and brain infraction together with hypertriglyceridemia. In relation to these hyperlipemias, diet therapy including limitation of lipid consumption within an appropriate range is of great importance, rather than drug therapy, which raises problems such as adverse side effects. However, patients under diet limitation suffer mental pain and must abandon the joy of their regular diet. Thus, complete diet therapy is difficult to attain, and the effect thereof is usually limited.
Excessive cholesterol in plasma accumulates on the inside of the blood vessels, inducing arteriosclerosis. However, if the cholesterol is taken up in the liver, and, then cholesterol and its metabolites, namely bile acid are excreted into the intestiral track without accumulation in the liver, followed by discharge together with feces to outside the body, the pool oize of cholesterol in the body decreases, to thereby prevent artheriosclerosis onset by the aforementioned mechanism. Thus, a cholesterol-lowering agent which exerts an effect for lowering hepatic cholesterol level as well as plasma cholesterol level has been desired.
A variety of microorganisms exerting a cholesterol-lowering effect with slight side effects are disclosed. However, yeasts are disclosed in surprisingly few number. From long ago, brewer's yeast has been known as a typical yeast, and its effect of improving lipid metabolism is disclosed in several literatures. For example, there are disclosed a case in which administration of chromium-added brewer's yeast (9 g/day) for eight weeks to elderly subjects decreased the serum cholesterol level [Ester G. Offenbacher and F. Xavier Pi-Sunyer, Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly subjects. Diabetes, 29, 919, (1980)]; a case in which administration of chromium chloride and brewer's yeast (5 g) for 10 weeks to elderly subjects caused no effect on the serum cholesterol level and triacylglycerol level [Caral J. Rinko, and F. Xavier Pi-Sunyer, The effects of inorganic chromium and brewer's yeast on glucose tolerance, plasma lipids, and plasma chromium in elderly subjects., Am. J. Clin. Nutr., 42, 454, (1985)]; and a case in which administration test of no-chromium-added brewer's yeast to human subjects resulted in no effect of lowering the serum cholesterol level [Arne T. Hostmark, Einar Eilertsen, and Ole Gronnerod, Plasma lipid and lipoprotein responses of rats to starch and sucrose diets with and without brewer's yeast., J. Nutri., 109, 1073, (1978)]. In addition, there is disclosed a case in which administration of a soybean-protein-added diet lowered the serum cholesterol level of rats, but a slight increase in the level was attained when 50% of the soybean protein was substituted by brewer's yeast [Jorge De Abreu and Nancy Millan, Effect of addition of brewer's yeast to soy protein and casein on plasma cholesterol levels of rabbits. Archivos Latinoamericanos de Nutricion., 44, 18, (1994)].
As described above, at present, there still remain different theories regarding the effect of brewer's yeast on improvement of lipid metabolism.
Effects of other yeasts are also disclosed in literature. For example, a methanol extract of Sporobolomyces ruberrinus and that of Saccharomyces uvarum are reported to slightly lower the serum cholesterol level and triglyceride level of choresterol-loaded rats (Shuji CHO, Hisao FUJII, and Jun Shiraishi, Effect of polysaccharide produced by Bacillus natto or alcohol extract of yeast on the lipid metabolism of rats. Bulletin of the Faculty of Home Life Science, Fukuoka Women's University, 16, 65, (1984)). Also disclosed is a case in which the culture supernatant of Saccharomyces cerebisiae lowers the serum cholesterol level of mice [Tadaaki Kishida, On the serum Cholesterol-Lowering Effect of Saccharomyces cerebisiae Liquid Culture. Jurnal of Japanese Society of Food and Nutrition, 26, 371, (1973)].
However, there is only a few reports in which effect of yeasts other than brewer's yeast or its constituent on improvement of lipid matabolism was demonstrated.
In the human liver, primary bile acids such as cholic acid and chenodeoxycholic acid are synthesized from cholesterol, and conjugated with glycine or taurine, to thereby yield glycine-conjugated or taurine-conjugated bile acid, which are secreted via the bile duct to the digestive tract. Bile acid causes lipid contained in foods and drinks to emulsify and disperse by its surface activation effect, and promotes digestion and absorption of lipid. The bile acid is then actively absorbed again from the ileum, returned to the liver via the portal vein, and resecreted to the digestive tract again. Thus, bile acids repeat enterohepatic circulation.
A portion of bile acid which has not been absorbed by the ileum undergoes modification by enterobacteria; e.g., deconjugation, 7α-dehydroxylation, oxidation, reduction, or epimerization, to thereby convert to secondary bile acid. Predominant secondary bile acids produced through the process are deoxycholic acid and lithocholic acid, which are formed by 7α-dehydroxylation of primary bile acids (cholic acid and chenodeoxycholic acid, respectively. A portion of secondary bile acid is passively absorbed by the large intestine and transferred to the liver, repeating enterohepatic-circulation in similar fashion to the case of primary bile acid. The remaining portion of secondary bile acid is excreted into feces.
In recent years, secondary bile acids such as deoxycholic acid and lithocholic acid produced by enterobacteria existing in the large intestinal tract have been found to be closely related to onset of colorectal cancer, liver cancer, pancreatic cancer, bile duct cancer, etc. In general, the carcinogenesis process is conceived to include an initiation step in which a gene is mutated by a chemical carcinogen, radiation, or a virus, and a promotion step in which abnormality occurs in growth and differentiation through long-term exposure to a promoter. Hitherto, there is disclosed that secondary bile acids such as deoxycholic acid and lithocholic acid act as a promoter in the second step, to thereby promote onset of colorectal cancer, liver cancer, pancreatic cancer, bile duct cancer, etc. (Narisawa, T., et al., J. Natl. Cancer Inst., 53, 1093-1097, 1974; Tsuda, H., et al., Gann, 75, 871-5, 1984; and Makino, T., et al., J. Natl. Cancer Inst., 76, 967-75, 1986). There is also disclosed that the carcinogenetic promoter activity of secondary bile acid is considerably stronger than that of primary bile acid (Narisawa, T., et al., J. Natl. Cancer Inst., 53, 1093-1097, 1974; and Reddy, B S., et al., Cancer Res., 37, 3238-3242, 1977). Moreover, there has recently been disclosed that deoxycholic acid may be related to onset of cholelithiasis other than cancers (Marcus, S N., Heaton, K W., Gut, 29, 522-533, 1988).
Thus, since secondary bile acids such as deoxycholic acid and lithocholic acid produced by enterobacteria existing in the large intestinal tract have a strong carcinogenetic promoter activity and cause cholelithiasis, diseases such as colorectalcancer, liver cancer, pancreatic cancer, bile duct cancer, and cholelithiasis can be prevented and treated through inhibition of secondary bile acid production.
Hitherto, secondary bile acid production inhibitors have been disclosed, even though the inhibitory effect is weak. These inhibitors are ampicillin—a type of penicillin derivative—(Low-Beer, T S., Nutter, S., Lancet, 2(8099), 1063-1065, 1978), 3α,12β-dihydroxy-5β-cholane-24-N-methylamine (Roda, A., et al., J. Pharm. Sci., 81, 237-240, 1992); lactulose—a type of oligosaccharide—(Magengast, F M., Eur. J. Clin. Invest., 18, 56-61, 1988); and wheat bran (Lampe, J W., et al., Gut, 34, 531-536, 1993).
Ampicillin and 3α,12β-dihydroxy-5β-cholane-24-N-methylamine inhibit secondary bile acid production by removing bacteria which catalyze 7α-dehydroxylation in the large intestinal tract. However, when these inhibitors are employed for a long period of time, there arise problems such as generation of resistant bacteria and occurrence of adverse side effects. In addition, selective exclusion of bacteria which relates to secondary bile acid production by use of antibiotics is impossible, and use of antibiotics simultaneously excludes enterobacteria which play an important role in maintaining the human health; e.g., Lactobacillus and Bifidobacterium, and this is greatly problematic.
Lactulose and wheat bran are thought to suppress activity of 7α-dehydroxylase which has optinal pH of a neutral region by lowering pH in the large intestinal track and thereby lower the production of secondary bile acid. However, these substances exert poor effectiveness, which does not reach the level for contributing to prevention and treatment of the diseases.
In view of the foregoing, an object of the present invention is to provide a cholesterol-lowering agent capable of effectively lowering the blood or hepatic cholesterol level by use of a safe yeast causing fewer and less severe side effects.
Another object of the present invention is to provide a secondary bile acid production inhibitor of high effectiveness and safety, useful for preventing and treating diseases such as colorectal cancer, liver cancer, pancreatic cancer, bile duct cancer, and cholelithiasis.